The non-steroidal anti-inflammatory drugs (NSAIDs) represent a class that is widely used in the treatment of various disorders. To date, treatment with NSAIDs is the best available therapy for pain caused by rheumatoid arthritis (RA) and osteoarthritis (OA), and other examples of common applications are treatment of fibromyalgia, of intestinal inflammation, inflammation of the urogenital tract and of the respiratory system, treatment of dysmenorrhoea and treatment of lupus erythematosus. Although the analgesic action of NSAIDs does not match in potency that of the opiates, their co-administration with usual narcotics has found wide application both for the treatment of postoperative pain and of chronic pain induced by various pathologies including tumoral pathologies. NSAIDs perform their anti-inflammatory and analgesic action via inhibition of cyclooxygenase (COX). At least two isoforms of COX are known: COX-1, expressed constitutively, and COX-2, which is absent from most tissues in physiological conditions and is expressed as a result of pro-inflammatory stimuli (e.g.: cytokines). As the traditional anti-inflammatories (tNSAIDs) are not selective, they inhibit both isoforms often with a preference for COX-1. This poor selectivity leads, with concomitant inhibition of COX-1, to inhibition of synthesis of prostanoids that are essential for maintenance of the functions of the gastric mucosa and of renal homeostasis, giving rise, especially in prolonged use, to severe gastrointestinal (GI) and renal complications. Inhibition of COX-1 by tNSAIDs leads initially to a decrease in thickness of the mucosa (erosion) and then to lesions (ulcer). At the renal level tNSAIDs are known to cause reduced glomerular filtration that gives rise to nephritides and, in particularly sensitive patients, to ischaemia and renal blockade. Clinical use of selective COX-2 inhibitors (Coxibs) has recently shown that the gastric toxicity associated with the use of tNSAIDs can be reduced considerably. Several recent clinical studies have shown that selective COX-2 inhibition, as well as giving rise to anti-inflammatories and analgesics with a safer GI profile, proves effective in the treatment of various precancerous and cancerous forms. In fact, COX-2 is overexpressed in gastric, hepatic, pancreatic, oesophageal, colon, breast, bladder, and lung tumours. However, various clinical and epidemiological studies have shown that long-term use of selective COX-2 inhibitors is associated with a higher incidence of adverse effects relating to the cardiovascular system, and in particular with an increased incidence of myocardial infarction, angina pectoris and transient ischaemic attacks. The cause of this toxicity for the cardiovascular system, which is also found with some tNSAIDs that are rather selective in inhibiting COX-2, arises from the fact that this isoform, constitutively expressed in the vascular epithelium, is fundamental to the synthesis of prostaglandin PGI2, a potent vasodilator (J. M. Dogné et al., J. Med. Chem., 2005, 48, 2251-2257). Thus, high selectivity in inhibition of COX-2 leads, in the cardiovascular system, to prevalence of the pro-aggregative and vasoconstrictive stimulus exerted by thromboxane (TxA2) no longer counterbalanced by the vasodilator effect of PGI2. The side effects associated with the use of tNSAIDs and those relating to the use of Coxibs create the need for new analgesics and anti-inflammatories that have a better profile of tolerability.
Similarly to prostacyclin (PGI2), nitric oxide (NO) at low concentrations has an important role in maintaining appropriate functionality of the cardiovascular system (J. F. Kervin et al., J. Med. Chem., 1995, 38, 4343-4362). Although the potent vasodilator effect of organic nitrates has been known for a long time, it was only discovered at the end of the 1970s that NO (Endothelium Derived Relaxing Factor, EDRF) is one of the mediators released by the vascular endothelium to control vasodilation, thrombosis, permeability and angiogenesis. NO gives rise, through activation of guanylate cyclase, to an increase in cGMP, which leads to vasodilation in smooth muscles, inhibits adhesion of leukocytes to the vessel wall and inhibits platelet aggregation, giving rise to an overall anti-thrombotic action.
It is also known that NO is of fundamental importance in maintaining good cardiac functionality and that gene knock-out experiments relating to the genes held to be responsible for expression of the enzymes capable of forming NO leads to spontaneous myocardial infarction (M. Tsutsui et al., Trends Cardiovasc. Med., 2008, 18, 8, 275-79). In the body, NO is synthesized by an enzyme known as nitric-oxide synthase (NOS), of which three isoforms are known: epithelial (eNOS), neuronal (nNOS) and inducible (iNOS). It is well known that appropriate derivatives of nitric acid (organic nitrates) as well as other organic compounds such as nitrosothiols and 1,2,5-oxadiazoles-2-oxide (furoxane N-oxide) are able to release NO of “exogenous” origin, so as to be utilizable in the treatment of cardiovascular pathologies (A. Martelli et al., Curr. Med. Chem. 2006, 13, 6, 609-25). The synthesis of molecules capable of selectively inhibiting COX-2 and at the same time of releasing NO appropriately, can give rise to new anti-inflammatory and analgesic drugs, without the cardiovascular and renal side effects that characterized the Coxibs. Some COX inhibitors that are donors of NO (CINOD: COX Inhibitors Nitric Oxide Donors) are known, for example naproxcinod (WO 9509831) and NO-flurbiprofen (WO 94012463). Although, for these products, complete absence of adverse events in the cardiovascular and renal area was recently claimed (WO 2008/132025), these compounds were designed more for overcoming the effects of gastric toxicity known for the COX-1 inhibitors than for the effects of cardiovascular and renal toxicity connected with inhibition of COX-2. In fact, protective effects exerted by NO are also known in the GI system, such as modulation of blood flow, control of permeability of the epithelium, secretion of mucus and of bicarbonate and capacity for improving the properties of self-repair in the damaged mucosa (J. L. Wallace et al., Trends Pharm. Sci., 2009, 30, 112-117). Selective COX-2 inhibitors that are at the same time NO donors have been reported, for example for rofecoxib (WO 2005/070883) or for cimicoxib (K. Chegaev et al., J. Med. Chem., 2007, 50, 1449-1457) as well as for other heterocyclic COX-2 inhibitors (C. Velazquez et al., Bioorg. & Med. Chem., 2005, 2749-2757). WO 2008/014821 describes inhibitors that are selective for COX-2, which have favourable pharmacokinetic and pharmacodynamic properties, which are reflected in excellent pharmacological properties. The possibility of combining, in these inhibitors, a function of being able to release NO appropriately, at the same time maintaining adequate activity in inhibition of COX-2, would give rise to new anti-inflammatory and analgesic drugs characterized by absence of the cardiovascular and renal effects typical of the selective COX-2 inhibitors, and would make it possible to improve their GI profile. Moreover, it should be borne in mind that although NO at high concentrations (such as the micromolar concentrations produced by iNOS) has deleterious effects on the cartilage in disorders such as OA and RA, at low concentrations (such as the nanomolar/picomolar concentrations produced by cNOS) NO has an anti-apoptotic and protective effect for the chondrocytes. Moreover, it is known that low concentrations of NO can have an important role in increasing blood flow, improving the supply of nutrients and oxygen to the synovia and to the subchondral bone. As well as the role of NO in the control of pain, via activation of cGMP in the nerve cells which, leading to hyperpolarization, consequently gives rise to blocking of pain transmission. These synergistic effects with inhibition of COX-2, exerted by release of small amounts of NO, are not only useful in the treatment of disorders such as OA and RA (I. S. Mackenzie et al., Arthritis Research & Therapy, 2008, 10: S3) but also in the treatment of various types of tumours (B. Bonavida et al., Nitric Oxide, 2008, 152-157). In fact, it was recently shown that NO-donors can inhibit the capacity of some types of tumours to metastasize as well as being able to restore apoptosis, making the tumour cell sensitive to chemotherapy. The role of nitro-aspirin (NO-ASA) in inhibiting the development of pancreatic tumour was described recently (N. Ouyang et al., Cancer Res., 2006, 66:8, 4503), as well as the efficacy of other CINODs in the treatment of colon tumour (G. K. Hagos et al., Mol. Cancer Ther., 2007, 2230-39) and prostate cancer (N. Beziere et al., Bioorganic & Med. Chem. Lett, 2008, 4655-57).